Anisomycin uses multiple mechanisms to stimulate mitogen-activated proteinkinases and gene expression and to inhibit neuronal differentiation in PC12 phaeochromocytoma cells

Treatment of PC12 cells with nerve growth factor (NGF) stimulates extracell ular signal-regulated kinases (ERKs), as well as stress-activated c-Jun N-t erminal kinases (JNKs) and p38 kinase, and induces neuronal differentiation . While the pivotal role of ERKs in NGF-induced morphological differentiati on is well established, the contribution of JNK- and p38-pathways is less c lear. The role of the JNK- and p38-pathway in PC12 cells was analysed by us ing anisomycin, a protein synthesis inhibitor that activates JNKs and p38. Non-toxic concentrations of anisomycin were found to stimulate these enzyme activities as well as the expression of the early response genes c-jun, c- fos and zif268, and to inhibit NGF-induced neurite formation. These effects of anisomycin appear to be mediated by the generation of reactive oxygen s pecies (ROS), which in turn act through both TrkA/Ras-dependent and -indepe ndent signalling pathways. In addition, cross-talk between the p38- and ERK -pathways appears to play a role in the action of anisomycin.